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Secondary amine

aShanxi Key Laboratory of Natural Products

& Pharmacy, Northwest A&F University, 22

China. E-mail: mxchang@@nwsuaf.edu.cnbCollege of Chemistry, Chemical Engineeri

Innovation Center of Functionalized Probes

Shandong, Shandong Normal University, 88

† Electronic supplementary information (See DOI: 10.1039/c9sc00323a

Cite this: Chem. Sci., 2019, 10, 4509

All publication charges for this articlehave been paid for by the Royal Societyof Chemistry

Received 20th January 2019Accepted 12th March 2019

DOI: 10.1039/c9sc00323a

rsc.li/chemical-science

This journal is © The Royal Society of C

s as coupling partners in directcatalytic asymmetric reductive amination†

Zitong Wu,a Shaozhi Du,a Guorui Gao,b Wenkun Yang,a Xiongyu Yang,a

Haizhou Huanga and Mingxin Chang *a

The secondary amine participating asymmetric reductive amination remains an unsolved problem in

organic synthesis. Here we show for the first time that secondary amines are capable of effectively

serving as N-sources in direct asymmetric reductive amination to afford corresponding tertiary chiral

amines with the help of a selected additive set under mild conditions (0–25 �C). The applied chiral

phosphoramidite ligands are readily prepared from BINOL and easily modified. Compared with common

tertiary chiral amine synthetic methods, this procedure is much more concise and scalable, as

exemplified by the facile synthesis of rivastigmine and N-methyl-1-phenylethanamine.

Introduction

Chiral amines are one of the most important classes ofcompounds displaying biological activities. In fact, about 40%of new chemical entities (NCEs) among FDA approved drugscontain chiral amine moieties.1 Tertiary amines account for60% of the total number of medicinal amines (a small selectionof chiral ones is shown in Fig. 1).2 Consequently, the develop-ment of efficient synthetic methods toward chiral amines,especially chiral tertiary amines, remains atop the organicchemists' priority list and it is an intensively studied and chal-lenging research area.3 In many cases chiral tertiary amines areprepared from the corresponding primary or secondary amines.Among those various methods, the protocols utilizing molec-ular hydrogen as the reductant, asymmetric hydrogenation (AH)of imine/enamine4 or iminium salts,5 and direct asymmetricreductive amination (DARA),4a,6 are preeminently attractive dueto their high atom economy and the vast available chiral ligandpool. In many cases, imines are difficult to prepare by AH andtheir instability operationally complicates the following reduc-tion (Scheme 1, route c). Currently DARA also takes a circuitousroute through primary amines to tertiary amines (Scheme 1,route b) and/or N-deprotection (Scheme 1, route a).

Reductive amination (RA) is nature's choice to synthesizeessential biomonomers including amino acids inside organ-isms,7 and the most practical method for the articial synthesis

& Chemical Biology, College of Chemistry

Xinong Road, Yangling, Shanxi 712100,

ng and Materials Science, Collaborative

for Chemical Imaging in Universities of

Wenhuadong Road, Jinan 250014, China

ESI) available: Procedures and spectra.

hemistry 2019

of pharmaceutical related and bulk fundamental amines.8 Asfor DARA, since its maiden voyage in the preparation ofherbicide metolachlor,9 progress has been made throughbiocatalysis,10 organocatalysis11 and transition-metal catal-ysis.12 This research journey is highlighted by its successfulapplication in the production of two pharmaceutical drugs,sitagliptin10a and suvorexant.12e Nevertheless, compared withthe prevailing utilization of achiral RA in both small-scalesynthesis and practical industrial production, DARA lagslargely behind. It requires revolutionary improvement inaspects of substrate scope and catalyst reactivity to makeDARA a general tool in chiral amine synthesis i.e., there are noreports on secondary amines as the N-source to constructtertiary chiral amines. If secondary amines are successfullyapplied in DARA as N-sources, chiral tertiary amines could beobtained directly without a detour (Scheme 1). The secondaryamine participating RA is considered as a challenge even in anachiral manner and typically requires high reaction tempera-ture (60 �C or above, even upto 120 �C).8c This difficulty prob-ably stems from the steric congestion during the imine/enamine formation and the reduction thereaer. Other chal-lenges include the formation of the alcohol side-product

Fig. 1 Selected chiral tertiary amine drugs.

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Table 1 Initial DARA investigation of acetophenone and pyrrolidinea

a Reaction conditions: Ir–L 1mol%, [Ir]/L (bisphosphine)¼ 1 : 1 or [Ir]/L(monophosphine) ¼ 1 : 2; 1a 0.2 mmol, 2a 0.2 mmol, solvent 2 mL, 60�C, 20 h; MS ¼ molecular sieves, 0.1 gram; TFA ¼ triuoroacetic acid;I2 10 mol%; yields and enantiomeric excesses were determined bychiral HPLC. b The solvent was EtOAc : CH2Cl2 ¼ 1 : 1 with theaddition of 10 mol% Et3N.

Scheme 1 Routes for the synthesis of chiral tertiary amines.

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resulting from ketone reduction and the steric-control issueowing to the possible E/Z isomers of the imine/enamineintermediates. We envisioned that two strategies may help toaddress these problems: (1) the addition of appropriateadditives which facilitate the imine/enamine intermediateformation,13 and (2) the application of robust and properlysized chiral ligands which could minimize the inhibitoryeffect of the amine starting material, imine/enamine inter-mediate and amine product, and at the same time stericallyaccommodate the bulky imine/enamine intermediates. Viathe proposed route, the efficiency of the synthesis of relatedimportant tertiary chiral amine intermediates and activepharmaceutical ingredients (APIs) would be greatlyenhanced.

Table 2 Examination of chiral monodentate phosphoramidite ligandsin DARA of acetophenone and pyrrolidinea

a Reaction conditions: [Ir]/L/1a/2a ¼ 1 : 2 : 100 : 100; 1a 0.1 mmol,solvent 2 mL, 60 �C, 20 h; MS ¼ molecular sieves, 0.1 gram; yieldswere isolated yields; enantiomeric excesses were determined by chiralHPLC. b 10 mol% 1,4-diazabicyclo[2.2.2]octane (DABCO) was addedinstead of Et3N; reaction solvent was DCM/THF/DCE (1 : 1 : 1.5);reaction temperature was room temperature. c The H2 pressure was 10atm. d The reaction temperature was 0 �C. e The catalyst loading was0.1 mol%.

Results and discussionEstablishment of feasibility

Molecular sieves, Brønsted acids12d and titanium iso-propoxide12b have been proven to be efficient additives in DARAto accelerate the formation of imine intermediates. At the sametime, molecular iodine is widely used in asymmetric hydroge-nation of imines.3b,13 So we selected molecular sieves (MS, 4 A),titanium isopropoxide (Ti(OiPr)4), and triuoroacetic acid (TFA)as the additive set with iridium-(R)-BINAP (Table 1, L1) as thecatalyst for the DARA of acetophenone 1a and pyrrolidine 2a.Unfortunately the reaction did not afford a satisfactory result(25% yield and 23% ee, Table 1, L1-1). Further investigationrevealed that basic Et3N was a better additive than triuoro-acetic acid. With the EtOAc and CH2Cl2 solvent pair, the yieldand ee were improved to 80% and 32%, respectively. Rh-(R)-BINAP furnished much lower ee compared with the corre-sponding iridium catalyst. From the brief screening of severalcommon chiral ligands, none of them engendered satisfactoryresults. Considering that the BINOL-based phosphoramiditeligands including PipPhos (Table 1, L5a) have been widelyapplied in asymmetric catalysis,14 and their highly attractivefeatures are that their two components, BINOL and the aminomoiety, are easily assembled together, and each part is highlymodulated, we decided to focus on this type of ligand.Exploiting the easiness of modication, we can tailor and ne-tune their steric and electronic properties for adapting ourspecic reaction.

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Evolution of chiral monodentate phosphoramidite ligands

Initially several chiral phosphoramidite ligands (Table 2, L5a–h)with different structural features were synthesized and appliedin the reductive coupling of 1a with 2a. It appeared that thebulky amino moiety on L5 positively impacted the enantiose-lectivity: from L5a to L5e, the ee value was improved from 24%

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Table 3 Exploration of the substrate scopea

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to 60%, then this trend reached a limit (Table 2, L5f, L5h) ataround 64% ee. So another strategy was required to furtherimprove the stereoselectivity. Taking full advantage of its easymodication feature, the 3,30-positions of the BINOL back-bonewere embedded with several common substituents (–Ph, –Me,–OMe and –CH2OMe) to synthesize ligands L6a–L9a. Fortu-nately this approach gave rise to better results. We observed thatthe enantioselectivity was boosted to 87%, in which L8a affor-ded the best result (85% yield and 87% ee). The improvementspecically functioned better for the piperidine moiety on thechiral ligands than for other groups (Table 2, L8a versus L8b–L8i). We postulated that it stems from the rigidity of thepiperidine ring structure. While the amino moiety possesseschirality, the steric conguration exerted signicant inuenceon the DARA enantioselectivity. Particularly when the 3,30-positions of the BINOL back-bone were embedded withsubstituents (Table 2, L8f versus L8g), the ee difference was ashigh as 38%. Further reaction condition optimization enhancedthe ee to 95% by replacing 10 mol% Et3N with the same amountof 1,4-diazabicyclo[2.2.2]octane (DABCO), changing the solventto THF/DCM/DCE (1 : 1 : 1.5), and decreasing the reactiontemperature to room temperature. We found that molecularsieves actually exerted no obvious inuence on the reaction.With 0.1 mol% of Ir–L8a at lower temperature (0 �C), the reac-tion still proceeded smoothly to further improve the enantio-selectivity to 97%. When the H2 pressure was decreased to 10atm, the desired product was obtained without noticeable lossof yield or stereoselectivity.

a Reaction conditions: [Ir]/L8a/1a/2a ¼ 1 : 2 : 100 : 110; 1a 0.3 mmol,total solvent volume 3 mL, 4 �C, 20 h; DABCO ¼ 1,4-diazabicyclo[2.2.2]octane; yields were isolated yields; enantiomeric excesses weredetermined by chiral HPLC or 1H NMR with a chemical shi reagent.b The applied ligand was (R)-L9a. c The reaction solvent was DMF/CH3CN/THF (1 : 1 : 1). d The applied solvent was acetonitrile/2-methyltetrahydrofuran 1 : 1. e The applied ligand was (Sa,Rc)-L9i.

f Theadditive set was: 10 mol% Et3N, 5 mol% I2; reaction solvent was DMF/CH3CN/THF 1 : 1 : 1; reaction temperature was room temperature.g The applied ligand was (R)-L10j. h 2 equiv. Ti(OiPr)4 was used; 10mol% Et3N was used instead of DABCO; reaction solvent was CH3CN/THF 4 : 1; reaction temperature was 12 �C; H2 pressure was 50 atm.

Examination of substrate scope

Under the established optimized reaction conditions, theapplicable substrate scope with respect to both various ketonesand amino coupling partners was investigated (Table 3). Theadditive set and catalytic system worked well for a series ofaromatic ketones (Table 3a). In general, the electronic proper-ties or positions of the substituent on the aromatic ringappeared to have limited effects on the experimental results.Regardless of whether the ketones have para-, meta-, or ortho-aryl substituents that are electron-donating (1c, 1k, and 1p),electron-withdrawing (1d, 1e, 1h, 1i, 1n, and 1r) or relativelysizeable (1g), the corresponding products were generated inexcellent yields of 87–98% and between 90% and 97% ee.Notably, sterically hindered ketones (1o–1r, 1t), which wereproblematic substrates for previously reported DARA reac-tions,11a,12m could be smoothly transformed into the desiredproducts without noticeable differences in yields and stereo-selectivity from less hindered substrates (3p versus 3c and 3rversus 3h). In addition, the polar and reducible group –NO2 (3h& 3r) was well-tolerated in the reactions. Moreover, the meth-odology worked fairly well for heteroaromatic ketone 1s (91%yield and 82% ee). The aryl–alkyl hybrid ketones 1v and 1w werenot suitable substrates, as only 6% and 3% ee were achieved for3v and 3w, respectively.

Other N-sources were also successfully applied in thismethod (Table 3B). Cyclic amines, morpholine 2b and tetrahy-droisoquinoline 2c, coupled with 1a efficiently to afford the

This journal is © The Royal Society of Chemistry 2019

desired products 3ab and 3ac with good yields and enantio-purity. Acyclic amines 2d, 2e and 2f also led to satisfactoryresults. Among the various alkylated amines, N-methyl-amines are of special interest because of their role in regu-lating biological functions.8c,15 We examined the DARA of 1awith N-methylbenzylamine 2f. This particular secondaryamine was selected as the N-source because benzyl is one of

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the most used N-protecting groups and could be easilyremoved with various readily available reagents. The corre-sponding N-methyl-N-benzyl-1-phenylethylamine product 3afwas obtained in excellent yield and enantioselectivity. Severalother N-methyl amines 2g–2j were also explored as the N-sources and good to excellent results were achieved. It isnoteworthy that the protic polar and acidic –OH group (1x)was well tolerated in this methodology. To better tsubstrates with different electronic and steric properties,reaction solvents and chiral ligands have been adjustedaccordingly. Acetonitrile, a polar solvent that has been rarelyutilized in asymmetric hydrogenation, along with 2-methyl-tetrahydrofuran gave better results for some meta- and ortho-substituted, bulkier and more polar substrates 1k, 1l, 1q, 1r,1t, 1ab and 1af than the DCM : THF : DCE solvent trio.Dimethyl formamide, another polar solvent, also workedbetter for amine sources other than pyrrolidine 2a (Table 3B).A chiral ligand with a longer side-arm L9a was applied for 1e,1g, and 1o, as L9i was used for various secondary amines 2b–2d and 2f–2j. The above results have demonstrated theversatility and power of the readily ne-tuned phosphor-amidite ligand series.

Practical applications

To further showcase the utility of this DARA strategy, we nextmade efforts on the synthesis of rivastigmine (API for Exelon,for the treatment of Alzheimer's type and Parkinson's typediseases and Lewy bodies, Fig. 1). Currently its industrialproduction depends on racemate resolution.16 Several efficientcatalytic asymmetric synthetic routes have been developed,including AH of the corresponding ketone,17 AH of N-methylimines11b and asymmetric hydroamination of alkynes,18 as thekey transformation. In comparison, our method is much moreefficient in terms of step-economy and operational simplicity.Starting from readily available and cheap meta-hydrox-yacetophenone 1x, (S)-rivastigmine was synthesized in 2 steps

Scheme 2 Practical application of DARA of secondary amines toprepare tertiary amines.

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with 92% overall yield and 91% ee (Scheme 2A). Moreover, withthe aforementioned N-methyl benzylamine 2c as the N-source,aer N-benzyl deprotection of the resulting product 3af fromthe DARA with 1a, N-methyl amine 4 could be obtained withoutlosing enantiopurity (Scheme 2B). This extended the applica-tion of this protocol to the synthesis of chiral secondary amines.The product 3ac, from 1a and tetrahydroisoquinoline 2c, couldbe further elaborated to synthesize the analogue of the naturalproduct and anti-tumor alkaloid (+)-crispine A (Scheme 2C).19

This reaction can easily be conducted on a large scale. Catalyzedwith 0.1 mmol% of Ir–L9i, the reductive amination of 1.20 g (10mmol) of ketone 1a and amine 2i gave 2.29 g of chiral amine 3ai(94% yield and 93% ee).

The above syntheses exemplify the versatility and potentialutilities of the DARA method for the expedited and straight-forward construction of important and/or medicinally relevantenantioenriched molecules.

Mechanism study

To gain insight into the reaction pathway, we conductedisotopic labeling experiments of 1a with 2h. From the 1H NMRintegration, using methyl deuterated substrate 1a, thedeuterium abundance at the chiral center C1 of 3ah was 7%and that on C2 was 41% (Scheme 3A). When applying deute-rium gas as the reductant, deuterium incorporation at the C1and C2 positions was 72% and 61%, respectively (Scheme 3B).The above results indicated that 1a and 2h formed theenamine intermediate, which underwent rapid tautomeriza-tion with the iminium form under the applied reactionconditions; also, the hydride addition to the iridium centerstep in the catalytic cycle was reversible. The results from theaddition of MeOD further conrmed the involvement of tau-tomerization and the reversibility of the hydride addition inthe reaction pathway (Scheme 3C). For non-aromatic ketones1t and 1u, two possible enamine intermediates may beformed, along with the E/Z isomers, resulting in inferiorstereoselectivity for the corresponding products. Although inour experiment the Ir/ligand ratio was 1 : 2, the 31P NMRspectra revealed only one P coordinated to Ir (see ESI†). Aerstirring the Ir–L9i complex in CDCl3 with 10 equiv. of Et3N for

Scheme 3 Deuterium incorporation studies.

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Scheme 4 Proposed reaction pathways.

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24 h, the 31P NMR spectrum displayed no obvious change,which excluded the possibility of cyclometalated iridiumcomplex formation.20 Based on the above results, we proposedthe possible reaction pathway (Scheme 4). With the help ofTi(OiPr)4, ketone 1 reacts with amine 2 to form the enamineintermediate int-1, which accepts a proton and transformsinto iminium int-2. int-1 and int-2 undergo fast interconver-sion. The iridium(I) complex I is oxidized to iridium(III) bymolecular iodine.21 Then DABCO or Et3N facilitates theheterolytic cleavage of the hydrogen molecule by iridium toform III. This step is reversible, which results in the hydrogenincorporation at C1 of 3ah (Scheme 3).

Conclusions

In summary, we have unprecedentedly applied secondaryamines as N-sources in direct catalytic asymmetric reductiveamination, thus providing a solution to an important and per-sisting problem in this research area. Accelerated by the addi-tive set and iridium–phosphoramidite ligand catalysts, theycoupled smoothly with various ketones to afford chiral tertiaryamines in excellent yields and high levels of stereocontrol.Benetting from the highly modulated feature of the BINOL-based phosphoramidite ligands, a variety of this series ofligands with divergent electronic and spatial properties couldbe rapidly developed to accommodate substrates with differentstructures for achieving excellent stereoselectivity. This meth-odology is operationally simple and cost-efficient with minimalsteps by utilizing readily available bulk chemicals. With ourprotocol, related chiral tertiary amines can be synthesized ina more convenient and effective manner.

Conflicts of interest

There are no conicts to declare.

This journal is © The Royal Society of Chemistry 2019

Acknowledgements

Financial support from the National Natural Science Founda-tion of China (21772155, 21402155 and 21602172) is gratefullyacknowledged.

Notes and references

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